The synthetic prostaglandin 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetranor PGF.sub.2.alpha. and its ester derivatives, in particular the isopropyl ester (2), are potent drugs for the treatment of glaucoma and ocular hypertension. Optimum therapeutic benefit is achieved when compound (2) is used in the form of the dextrorotatory single enantiomer (+)-2, as depicted below. For development as a pharmaceutical product, an economically viable route is required for the synthesis of (+)-2 in quantities of at least 1 kg. ##STR2##
EP-A-0639563 describes biological studies of compound 2 and analogues, and synthetic methods which are applicable to its preparation. The synthetic strategy employed is based on that used by Corey in his pioneering synthesis of prostaglandin F.sub.2.alpha. (Corey and Cheng, The Logic of Chemical Synthesis, Wiley, 1989, p. 250-266 and references therein), wherein the cyclopentane ring embedded in a lactone intermediate of type 3 (PG=protecting group, e.g. Me) has relative stereochemistry correctly defined across four chiral centres. Lactones of type 3 can be prepared in single enantiomer form. Although such a route was successfully utilised to prepare small quantities of (+)-2 for preliminary biological evaluation, for a number of reasons it is unsuitable for industrial manufacture as a high-purity pharmaceutical product for administration to human patients. At least 15 steps (from cyclopentadiene) are required, with loss of yield in individual steps exacerbated by the linear nature of the synthesis. Fractional column chromatography is required after many of these steps to effect purification of intermediates. For example, a late stage stereoselective reduction of a 15-keto function in the .omega.-side chain using (-)-B-chlorodiisopinocampheylborane requires the removal of the unwanted 15S isomer, formed as a by-product, by a chromatographic separation. ##STR3##
An alternative and more convergent approach to prostaglandins involves addition of a cuprate reagent, incorporating the entire .omega.-side chain, to the tricyclo[3.2.0.0.sup.2,7 ]heptanone 4 (Lee el al, J. Chem. Soc., Perkin Trans 1, 1978,1176). Tricyclic ketone 4 is prepared from a TBDMS-protected bromohydrin which is in turn derived from bicyclo[3.2.0]hept-2-en-6-one (5). In comparison to routes proceeding by a Corey lactone of type 3, significantly fewer steps are required. For example, preparation of prostaglandin F.sub.2.alpha. from compound 5 requires only 8 steps (10 steps from cyclopentadiene). Avoidance of awkward late-stage reduction to establish the required configuration of the C-15-OH functionality provides another advantage.
EP-A-0074856 describes resolution of racemic bicyclo[3.2.0]hept-2-en-6-one (5) by forming diastereomeric salts of its .alpha.-hydroxysulfonic acid derivative with a chiral amine, and separation by crystallisation.
Certain lactones are described in Newton et al, Tetrahedron, 1980, 2163. None is crystalline.